CTLA4-Ig Restores Rejection of MHC Class-II Mismatched Allografts by Disabling IL-2-Expanded Regulatory T Cells

Allograft acceptance and tolerance can be achieved by different approaches including inhibition of effector T cell responses through CD28-dependent costimulatory blockade and induction of peripheral regulatory T cells (Tregs). The observation that Tregs rely upon CD28-dependent signals for development and peripheral expansion, raises the intriguing possibility of a counterproductive consequence of CTLA4-Ig administration on tolerance induction. We have investigated the possible negative effect of CTLA4-Ig on Treg-mediated tolerance induction using a mouse model of single MHC class II-mismatched skin grafts in which long-term acceptance was achieved by short-term administration of IL-2/anti-IL-2 complex. CTLA4-Ig treatment was found to abolish Treg-dependent acceptance in this model, restoring skin allograft rejection and Th1 alloreactivity. CTLA4-Ig inhibited IL-2-driven Treg expansion, and prevented in particular the occurrence of ICOS(+) Tregs endowed with potent suppressive capacities. Restoring CD28 signaling was sufficient to counteract the deleterious effect of CTLA4-Ig on Treg expansion and functionality, in keeping with the hypothesis that costimulatory blockade inhibits Treg expansion and function by limiting the delivery of essential CD28-dependent signals. Inhibition of regulatory T cell function should therefore be taken into account when designing tolerance protocols based on costimulatory blockade. Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons

Rats Acquire Stronger Preference for Flavors Consumed Towards the End of a High-fat Meal

Rats learn to prefer flavors associated with postingestive effects of nutrients. The physiological signals underlying this postingestive reward are unknown. We have previously shown that rats readily learn to prefer a flavor that was consumed early in a multi-flavored meal when glucose is infused intragastrically (IG), suggesting rapid postingestive reward onset. The present experiments investigate the timing of postingestive fat reward, by providing distinctive flavors in the first and second halves of meals accompanied by IG fat infusion. Learning stronger preference for the earlier or later flavor would indicate when the rewarding postingestive effects are sensed. Rats consumed sweetened, calorically-dilute flavored solutions accompanied by IG high-fat infusion (+ sessions) or water (− sessions). Each session included an “Early” flavor for 8 min followed by a “Late” flavor for 8 min. Learned preferences were then assessed in two-bottle tests (no IG infusion) between Early(+) vs. Early(−), Late(+) vs. Late(−), Early(+) vs. Late(+), and Early(−) vs. Late(−). Rats only preferred Late(+), not Early(+), relative to their respective (−) flavors. In a second experiment rats trained with a higher fat concentration learned to prefer Early(+) but more strongly preferred Late(+). Learned preferences were evident when rats were tested deprived or recently satiated. Unlike with glucose, ingested fat appears to produce a slower-onset rewarding signal, detected later in a meal or after its termination, becoming more strongly associated with flavors towards the end of the meal. This potentially contributes to enhanced liking for dessert foods, which persists even when satiated.

Rats' Learned Preferences for Flavors Encountered Early or Late in a Meal Paired with the Postingestive Effects of Glucose

Rats learn to prefer flavors that are followed by postingestive effects of nutrients. This experiment investigated whether the timing of a flavor (specifically, in the first or second half of the meal) influences learning about that flavor. Stronger learning about earlier or later flavorswould indicate when the rewarding postingestive effects of nutrients are sensed. Ratswith intragastric (IG) catheters drank saccharin-sweetened, calorically-dilute solutions with distinct flavors added, accompanied by IG infusion of glucose (+sessions) or water (−sessions). In both types of sessions, an “Early” flavorwas provided for the first 8 min and a “Late” flavor for the last 8 min. Thus, rats were trained with Early(+) and Late(+) in high-caloriemeals, and Early(−) and Late(−) in low-calorie meals. Strength of the learned preference for Early(+) and Late(+) was then assessed in a series of two-bottle choice tests between Early(+) vs. Early(−), Late(+) vs. Late(−), Early(+) vs. Late(+), and Early(−) vs. Late(−). Rats preferred both Early(+) and Late(+) over the respective (−) flavors. But Early(+)was only preferredwhen rats were tested hungry. Late(+) was preferred when rats were tested hungry or recently satiated. This indicates qualitatively different associations learned about flavors at different points in themeal.While not supporting the idea that postingestive effects become most strongly associated with later-occurring (“dessert”) flavors, it does suggest a reason dessert flavors may remain attractive in the absence of hunger.

Sensory-specific Appetition: Postingestive Detection of Glucose Rapidly Promotes Continued Consumption of a Recently Encountered Flavor

It is generally thought that macronutrients stimulate intake when sensed in the mouth (e.g., sweet taste) but as food enters the GI tract its effects become inhibitory, triggering satiation processes leading to meal termination. Here we report experiments extending recent work (see [1]) showing that under some circumstances nutrients sensed in the gut produce a positive feedback effect, immediately promoting continued intake. In one experiment, rats with intragastric (IG) catheters were accustomed to consuming novel flavors in saccharin daily while receiving water infused IG (5 ml/15 min). The very first time glucose (16% w/w) was infused IG instead of water, intake accelerated within 6 mins of infusion onset and total intake increased 29% over baseline. Experiment 2 replicated this stimulatory effect with glucose infusion but not fructose nor maltodextrin. Experiment 3 showed the immediate intake stimulation is specific to the flavor accompanying the glucose infusion. Rats were accustomed to flavored saccharin being removed and replaced with the same or a different flavor. When glucose infusion accompanied the first bottle, intake from the second bottle was stimulated only when it contained the same flavor, not when the flavor switched. Thus we confirm not only that glucose sensed postingestively can have a rapid, positive feedback effect ('appetition' as opposed to 'satiation') but that it is sensory-specific, promoting continued intake of a recently encountered flavor. This sensory specific motivation may represent an additional psychobiological influence on meal size, and further, has implications for the mechanisms of learned flavor-nutrient associations.

Rats Acquire Stronger Preference for Flavors Consumed Towards the End of a High-fat Meal

Rats learn to prefer flavors associated with postingestive effects of nutrients. The physiological signals underlying this postingestive reward are unknown. We have previously shown that rats readily learn to prefer a flavor that was consumed early in a multi-flavored meal when glucose is infused intragastrically (IG), suggesting rapid postingestive reward onset. The present experiments investigate the timing of postingestive fat reward, by providing distinctive flavors in the first and second halves of meals accompanied by IG fat infusion. Learning stronger preference for the earlier or later flavor would indicate when the rewarding postingestive effects are sensed. Rats consumed sweetened, calorically-dilute flavored solutions accompanied by IG high-fat infusion (+ sessions) or water (- sessions). Each session included an "Early" flavor for 8min followed by a "Late" flavor for 8min. Learned preferences were then assessed in two-bottle tests (no IG infusion) between Early(+) vs. Early(-), Late(+) vs. Late(-), Early(+) vs. Late(+), and Early(-) vs. Late(-). Rats only preferred Late(+), not Early(+), relative to their respective (-) flavors. In a second experiment rats trained with a higher fat concentration learned to prefer Early(+) but more strongly preferred Late(+). Learned preferences were evident when rats were tested deprived or recently satiated. Unlike with glucose, ingested fat appears to produce a slower-onset rewarding signal, detected later in a meal or after its termination, becoming more strongly associated with flavors towards the end of the meal. This potentially contributes to enhanced liking for dessert foods, which persists even when satiated.